The role of female sex hormones in various immune mediated disorders has been the subject of various scientific publications. It has been recognised that autoimmune diseases such as multiple sclerosis and rheumatoid arthritis preferentially affect women (Jansson et al., Inflamm Res 1998 July; 47(7): 290-301). In addition the observation has been made that during pregnancy, when levels of female sex hormones are high, clinical remissions of cell-mediated autoimmune diseases are common, with disease exacerbation often seen post-partum when sex hormone levels are low (Kim et al., Neurology 1999 Apr. 12; 52(6) 1230-1238). Furthermore it has been reported that an unusually high fraction of patients with multiple sclerosis show decreased gonadotropin and estrogen values in the urine (Poser et al., Geburtshilfe Frauenhielkd 1981 May; 41(5): 353-358).
Furthermore studies in castrated mice have shown that administration of estradiol and estriol in an amount which induces the serum levels seen at late stage pregnancy, delays the onset of experimental autoimmune encephalomyelitis (EAE), a Th1 cell-dependent autoimmune disease used as a model of multiple sclerosis (Jansson et al., Inflamm Res 1998 July; 47(7): 290-301). The results of an evaluation of the effect of 17β-estradiol on gene expression in EAE using DNA microarray implicate a limited set of known and previously unsuspected estradiol-sensitive genes that may be crucial for inhibition of EAE and potentially the human disease, multiple sclerosis (Matejuk et al., Endocrinology 2002 January; 143(1): 313-319).
WO 01/185154 relates to a method of ameliorating a Th1-mediated immune pathology in a mammal by administering a low dose of estrogen to the mammal, particularly a low dose of 17β-estradiol, estriol or estrone. Low doses of these estrogens are deemed necessary to avoid the potential adverse effects of high levels of estrogen on the reproductive and circulatory systems and also to prevent unwanted side effects in males.
The aforementioned estrogens 17β-estradiol, estriol and estrone have in common that they are endogenous to the female body, i.e. they are biogenic estrogens. These biogenic estrogens show serious pharmacokinetic deficits. Their oral bio-availability is very low and varies greatly from person to person, meaning that general dosage recommendations cannot be given. Fast elimination of these estrogens from the blood is another related problem. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate (daily) administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
In addition to pharmacokinetic problems, the known estrogens also show pharmacodynamic deficits. After resorption from the intestinal lumen, orally applied active ingredients enter the organism via the liver. This fact is of specific importance for estrogenic agents as the liver is a target organ for estrogens; oral intake of estrogens results in strong estrogenic effects in the liver. The secretion activity that is controlled by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. If biogenic estrogens are introduced to the female organism while avoiding passage through the liver (e.g. by transdermal application), the liver functions mentioned remain largely unchanged. Therapeutically equivalent doses of commonly known biogenic estrogens, when applied orally, result in clear responses of hepatic parameters, such as increase of SHBG, CBG, angiotensinogen and HDL (high density lipoprotein).
Consequently there is a need for estrogenic substances that:
(a) are more effective in a method of treating immune mediated diseases as the aforementioned biogenic estrogens and/or
(b) have a significantly longer halflife than the aforementioned biogenic estrogens and/or
(c) are orally administerable without causing significant hepatic effects and/or
(d) produce less undesirable side-effects than the aforementioned biogenic estrogens.